Presentation on theme: "Renal Replacement Therapy Childrens Healthcare of Atlanta."— Presentation transcript:
Renal Replacement Therapy Childrens Healthcare of Atlanta
Renal Replacement Therapy What is it? –The medical approach to providing the electrolyte balance, fluid balance, and toxin removal functions of the kidney. How does it work? –Uses concentration and pressure gradients to remove solutes (K, Urea, etc…) and solvents (water) from the human body.
Where did it come from? In Germany during 1979, Dr. Kramer inadvertently cannulated the femoral artery of a patient which led to a spontaneous experiment with CAVH (continuous arteriovenous hemofiltration) –The patient's cardiac function alone is capable of driving the system –Large volumes of ultrafiltrate were produced through the highly permeable hemofilter –Continuous arteriovenous hemofiltration could provide complete renal replacement therapy in an anuric adult
History of Pediatric Hemofiltration USA, 1985: Dr. Liebermann used SCUF (slow continuous ultrafiltration) to successfully support an anuric neonate with fluid overload Italy, 1986: Dr. Ronco described the successful use of CAVH in four neonates USA, 1987: Dr. Leone described CAVH in older children 1993: A general acceptance of pump-driven CVVH was seen as less problematic than CAVH
In 1984, Dr. Claudio Ronco, treated this child with CAVH in Vicenza, Italy. This is the first patient purposely treated with CAVH in the world. The patient survived.
Mechanisms of Action: Convection Hydrostatic pressure pushes solvent across a semi-permeable membrane Solute is carried along with solvent by a process known as solvent drag Membrane pore size limits molecular transfer Efficient at removal of larger molecules compared with diffusion Pressure Na H2OH2OH 2 O + Na
Solvent moves up a concentration gradient Solute diffuses down an concentration gradient –Solute movement occurs via Brownian motion The smaller the molecule (e.g. urea) the greater the kinetic energy The larger the concentration gradient the more drive for movement Therefore, smaller molecules with greater concentration gradients move more quickly across membrane Mechanisms of Action: Diffusion Osmolarity H2OH2OH2OH2O Urea Uremia
Semi-permeable Membranes –Urea –Creatinine –Uric acid –Sodium –Potassium –Ionized calcium –Phosphate –Almost all drugs not bound to plasma proteins Allow easy transfer of solutes less than 100 Daltons –Bicarbonate –Interleukin-1 –Interleukin-6 –Endotoxin –Vancomycin –Heparin –Pesticides –Ammonia Are impermeable to albumin and other solutes of greater than 50,000 Daltons
Semi-permeable Membranes Sieving Coefficient –Defines amount (clearance) of molecule that crosses semi-permeable membrane Sieving Coefficient is 1 for molecules that easily pass through the membrane and 0 for those that do not
Semi-permeable Membranes Continuous hemofiltration membranes consist of relatively straight channels of ever-increasing diameter that offer little resistance to fluid flow Intermittent hemodialysis membranes contain long, tortuous inter-connecting channels that result in high resistance to fluid flow
How is it done? Peritoneal Dialysis Hemodialysis Hemofiltration The choice of which modality to use depends on –Patients clinical status –Resources available
Peritoneal Dialysis Fluid placed into peritoneal cavity by catheter Glucose provides solvent gradient for fluid removal from body Can vary concentration of electrolytes to control hyperkalemia Can remove urea and metabolic products Can be intermittent or continuously cycled
Peritoneal dialysis Simple to set up & perform Easy to use in infants Hemodynamic stability No anti-coagulation Bedside peritoneal access Treat severe hypothermia or hyperthermia Unreliable ultrafiltration Slow fluid & solute removal Drainage failure & leakage Catheter obstruction Respiratory compromise Hyperglycemia Peritonitis Not good for hyperammonemia or intoxication with dialyzable poisons AdvantagesDisadvantages
Intermittent Hemodialysis Maximum solute clearance of 3 modalities Best therapy for severe hyperkalemia Limited anti-coagulation time Bedside vascular access can be used Hemodynamic instability Hypoxemia Rapid fluid and electrolyte shifts Complex equipment Specialized personnel Difficult in small infants AdvantagesDisadvantages
Continuous Hemofiltration Easy to use in PICU Rapid electrolyte correction Excellent solute clearances Rapid acid/base correction Controllable fluid balance Tolerated by unstable patients Early use of TPN Bedside vascular access routine Systemic anticoagulation (except citrate) Frequent filter clotting Vascular access in infants AdvantagesDisadvantages
SCUF:Slow Continuous Ultrafiltration Blood is pushed through a hemofilter Pressure generated within filter pushes solvent (serum) through semi-permeable membrane (convection) Solutes are carried through membrane by a process known as solvent drag UreaCreatinine KNaH2OH2O Blood Ultrafiltrate Pressure Control rate of fluid removal
SCUF:Slow Continuous Ultrafiltration Pros –Filters blood effectively –Control fluid balance by regulating transmembrane pressures –No replacement fluid therefore less pharmacy cost Cons –No replacement fluid given so electrolyte abnormalities can occur –Low ultrafiltration rates that keep electrolytes balanced do not remove urea effectively
CVVH Blood is pushed through a hemofilter Pressure within filter (convection) Solvent Drag UreaCreatinine KNaH2OH2O Ultrafiltrate Replacement Fluid Blood Pressure Replacement fluid given back to patient
Continuous Venovenous Hemofiltration Filtration occurs by convection Mimics physiology of the mammalian kidney –Provides better removal of middle molecules (500-5000 Daltons) thought to be responsible clinical state of uremia Ultrafiltrate is replaced by a sterile solution (replacement solution) Patient fluid loss (or gain) results from the difference between ultrafiltration and replacement rates
CVVHD Blood is pushed through a hemofilter UreaCreatinine KNaH2OH2O Dialysate Blood Dialysis Fluid Dialysis fluid flows counter- current to blood flow Water and Solutes move across concentration gradients (diffusion)
Continuous Venovenous Hemodialysis Diffusion (predominantly) –Some convection occurs due to transmembrane pressure created by roller-head pump Dialysate flow rate is slower than BFR and is the limiting factor to solute removal –Therefore, solute removal is directly proportional to dialysate flow rate
CVVHDF UreaCreatinine KNaH2OH2O Replacement Fluid Blood Dialysis FluidDialysate Pressure Blood is pushed through a hemofilter Dialysis fluid flows counter- current to blood flow Water and Solutes move across concentration gradients (diffusion) Pressure within filter (convection) Solvent Drag Replacement fluid given back to patient
Continuous Venovenous Hemodialysis with Ultrafiltration Pros –Can provide both ultrafiltration (removal of medium size molecules) and dialysis (removal of small molecules) –Can remove toxins Cons –Toxin removal is slow –Overly complicated to set-up for small clinical benefits
Is there a Best Method? The greatest difference between modalities is most likely related to the membrane utilized and their specific characteristics. There are no data available assessing patient outcomes using diffusive (CVVHD) and convective (CVVH) therapies
Indications for Renal Replacement Therapy Intractable acidosis Fluid overload or pulmonary edema BUN > 150 mg/dL Symptomatic uremia (encephalopathy, pericarditis) Hyperkalemia (serum K > 7 mEq/L) Hyperammonemia Ultrafiltration for nutritional support or excessive transfusions Exogenous toxin removal Hyponatremia or hypernatremia Adapted From Rogers Textbook of Pediatric Intensive Care, Table 38.7
Filtration Fraction The degree of blood dehydration can be estimated by determining the filtration fraction (FF) –The fraction of plasma water removed by ultrafiltration FF(%) = (UFR x 100) / QP where QP is the filter plasma flow rate in ml/min QP = BFR* x (1-Hct) *BFR: blood flow rate
Ultrafiltrate Rate FF(%) = (UFR x 100) / QP QP = BFR x (1-Hct) For example... –When BFR = 100 ml/min & Hct = 0.30 (i.e. 30%), the QP = 70 ml/min –A filtration fraction > 30% promotes filter clotting –In this example, when the maximum allowable FF is set at 30%, a BFR of 100 ml/min yields a UFR = 21 ml/min QP: the filter plasma flow rate in ml/min
Blood Flow Rate & Clearance A child with body surface area = 1.0 m 2, BFR = 100 ml/min and FF = 30% –Small solute clearance is 36.3 ml/min/1.73 m 2 (About one third of normal renal small solute clearance) Target CVVH clearance of at least 15 ml/min/1.73 m 2 –For small children, BFR > 100 ml/min is usually unnecessary –High BFR may contribute to increased hemolysis within the CVVH circuit
Pediatric CRRT Vascular Access: Performance = Blood Flow!!! Minimum 30 to 50 ml/min to minimize access and filter clotting Maximum rate of 400 ml/min/1.73m 2 or –10-12 ml/kg/min in neonates and infants –4-6 ml/kg/min in children –2-4 ml/kg/min in adolescents
Urea Clearance Urea clearance (C urea) in hemofiltration, adjusted for the patient's body surface area (BSA), can be calculated as follows: C urea = UF [urea] x UFR x 1.73 BUNpts BSA In CVVH, ultrafiltrate urea concentration and BUN are the same, canceling out of the equation, which becomes: C urea = UFR x 1.73 pts BSA C urea: (ml/min/1.73 m 2 BSA)
Urea Clearance When target urea clearance (C urea) is set at 15 ml/min/1.73 m2, the equation can be solved for UFR 15 = UFR x 1.73 / pts BSA UFR = 15 / 1.73 = 8.7 ml/min Thus, in a child with body surface area = 1.0 m 2, a C urea of about 15 ml/min/1.73 m 2 is obtained when UFR = 8.7 ml/min or 520 ml/hr. This same clearance can be achieved in the 1.73 m 2 adolescent with a UFR = 900 ml/hr.
Solute Molecular Weight and Clearance Solute (MW)Convective Coefficient Diffusion Coefficient Urea (60)1.01 ± 0.05 1.01 ± 0.07 Creatinine (113)1.00 ± 0.09 1.01 ± 0.06 Uric Acid (168)1.01 ± 0.04 0.97 ± 0.04 Vancomycin (1448)0.84 ± 0.10 0.74 ± 0.04 Cytokines (large)adsorbed minimal clearance Drug therapy can be adjusted by using frequent blood level determinations or by using tables that provide dosage adjustments in patients with altered renal function
Fluid Balance Precise fluid balance is one of the most useful features of CVVH Each hour, the volume of filtration replacement fluid (FRF) is adjusted to yield the desired fluid balance.
Replacement Fluids Ultrafiltrate can be replaced with a combination of: –Custom physiologic solutions –Ringers lactate –Total parenteral nutrition solutions In patients with fluid overload, a portion of the ultrafiltrate volume is simply not replaced, resulting in predictable and controllable negative fluid balance.
Anticoagulation To prevent clotting within the CVVH circuit, active anti-coagulation is often needed –Heparin –Citrate –Local vs. systemic
Mechanisms of Filter Thrombosis CONTACT PHASE XII activation XI IX TISSUE FACTOR TF:VIIa THROMBIN fibrinogen prothrombin XaVaVIIIa Ca ++ platelets CLOT monocytes / platelets / macrophages FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION NATURAL ANTICOAGULANTS (APC, ATIII) X Phospholipid surface Ca + +
Sites of Action of Heparin CONTACT PHASE XII activation XI IX TISSUE FACTOR TF:VIIa THROMBIN fibrinogen prothrombin Xa VaVIIIa Ca ++ platelets CLOT monocytes platelets macrophages FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION NATURAL ANTICOAGULANTS (APC, ATIII) X Phospholipid surface Ca + + UF HEPARIN ATIII
Heparin - Problems Bleeding Unable to inhibit thrombin bound to clot Unable to inhibit Xa bound to clot Ongoing thrombin generation Direct activation of platelets Thrombocytopenia Extrinsic pathway unaffected
No HeparinSystemically Heparinized NO surface - no heparin NO surface - heparinized Compliments of Dr. Gail Annich, University of Michigan
Hoffbauer R et al. Kidney Int. 1999;56:1578-1583. Unfractionated Heparin
Sites of Action of Citrate CONTACT PHASE XII activation XI IX TISSUE FACTOR TF:VIIa THROMBIN fibrinogen prothrombin Xa VaVIIIa Ca ++ platelets CLOT monocytes / platelets / macrophages FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION NATURAL ANTICOAGULANTS (APC, ATIII) X Phospholipid surface Ca + + CITRATE
Anticoagulation: Citrate Citrate regional anticoagulation of the CVVH circuit may be employed when systemic (i.e., patient) anticoagulation is contraindicated for any reason (usually, when a severe coagulopathy pre-exists). CVVH-D helps prevent inducing hypernatremia with the trisodium citrate solution
Anticoagulation: citrate Citrate regional anticoagulation of the CVVH circuit: –4% trisodium citrate pre-filter –Replacement fluid: normal saline –Calcium infusion: 8% CaCl in NS through a distal site Ionized calcium in the circuit will drop to < 0.3, while the systemic calcium concentration is maintained by the infusion.
Citrate Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.
Citrate: Problems Metabolic alkalosis –metabolized in liver / skeletal muscle / other tissues Electrolyte disorders –Hypernatremia –Hypocalcemia –Hypomagnesemia May not be able to use in –Congenital metabolic diseases –Severe liver disease / hepatic failure May be issue with massive blood transfusions
Experimental: High Flow High-volume CVVH might… –Improve hemodynamics –Increase organ blood flow –Decrease blood lactate and nitrite/nitrate concentrations.
Ronco et al. Lancet 2000; 351: 26-30 35 mL/kg/hr ~ 40 cc/min/1.73 m 2
Ronco et al. Lancet 2000; 351: 26-30 Conclusions: –Minimum UF rates should reach at least 35 ml/kg/hr (40 mL/min/1.73 m 2 ) –Survivors in all their groups had lower BUNs than non-survivors prior to commencement of hemofiltration
Experimental: septic shock Zero balance ultrafiltration (ZBUF) performed –3L ultrafiltrate/h for 150 min then 6 L/h for an additional 150 min. Rogers et al: Effects of CVVH on regional blood flow and nitric oxide production in canine endotoxic shock.
What are the targets? Most known mediators are water soluble Possible contenders –500-60,000D (middle molecules) cytokines anti/pro-coagulants –Other molecules complement phospholipase A-2 dependent products Likely many unknown contenders
Unknowns of Hemofiltration for Sepsis Interaction of immune system with foreign surface of the circuit? –Complement activation –Bradykinin generation –Leukocyte adhesion Clearance of anti-inflammatory mediators? Clearance of unknown good mediators? What do plasma levels of mediators really mean? Is animal sepsis clinically applicable to human sepsis?
Clinical Applications in Pediatric ARF: Disease and Survival Bunchman TE et al: Ped Neph 16:1067-1071, 2001
Clinical Applications in Pediatric ARF: Disease and Survival Patient survival on pressors (35%) lower survival than without pressors (89%) (p<0.01) Lower survival seen in CRRT than in patients who received HD for all disease states Bunchman TE et al: Ped Neph 16:1067-1071, 2001
Pediatric CRRT in the PICU 22 pt (12 male/10 female) received 23 courses (3028 hrs) of CVVH (n=10) or CVVHD (n=12) over study period. Overall survival was 41% (9/22). Survival in septic patients was 45% (5/11). PRISM scores at ICU admission and CVVH initiation were 13.5 +/- 5.7 and 15.7 +/- 9.0, respectively (p=NS). Conditions leading to CVVH (D) –Sepsis (11) –Cardiogenic shock (4) –Hypovolemic ATN (2) –End Stage Heart Disease (2) –Hepatic necrosis, viral pneumonia, bowel obstruction and End- Stage Lung Disease (1 each) Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
Percent Fluid Overload Calculation % FO at CVVH initiation = [ Fluid In - Fluid Out ICU Admit Weight ] * 100% Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
Renal Replacement Therapy in the PICU Pediatric Literature Lesser % FO at CVVH (D) initiation was associated with improved outcome (p=0.03) Lesser % FO at CVVH (D) initiation was also associated with improved outcome when sample was adjusted for severity of illness (p=0.03; multiple regression analysis) Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
PRISM at CRRT Initiation and Outcome P < 0.0005
Fluid Overload and Outcome: Renal Failure Only P < 0.05
Final Thoughts on Hemofiltration Medical Therapy that can perform the functions of the kidney and provide precise electrolyte and fluid balance Unknown which method (CVVH vs. CVVHD vs. CVVHDF) is best Many applications in the PICU No perfect method of coagulation High flow replacement fluids may be beneficial in sepsis Earlier use in fluid overloaded patients with lower PRISM scores may improve mortality
These slides created from presentations by... Joseph DiCarlo, MD Stanford University Steven Alexander, MD Stanford University Catherine Headrick, RN Childrens Medical Center Dallas Patrick D. Brophy, MD University of Michigan Peter Skippen, MD British Columbia Childrens Hospital Stuart L. Goldstein, MD Baylor College of Medicine Timothy E. Bunchman, MD University of Alabama